Role of IKKalpha in lung squamous cell carcinoma development. Lung cancer is the leading cause of cancer mortality worldwide; however, there are no robust animal models of lung squamous cell carcinomas (SCCs), one of the major types of lung cancer. We report that kinase-dead IKKalpha knock-in mice develop spontaneous lung SCCs associated with IKKalpha downregulation and marked pulmonary inflammation. IKKalpha reduction upregulated the expression of p63, Trim29, and keratin 5 (K5), which serve as diagnostic markers for human lung SCCs. IKKalphalowK5+p63hi cell expansion and SCC formation were accompanied by inflammation-associated deregulation of oncogenes, tumor suppressors, and stem cell regulators. Reintroducing transgenic K5.IKKalpha, depleting macrophages, and reconstituting irradiated mutant animals with WT bone marrow (BM) prevented SCC development, suggesting that BM-derived IKKalpha-mutant macrophages promote the transition of IKKalphalowK5+p63hi cells to tumor cells. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs.